Genotype–phenotype associations in 1018 individuals with SCN1A‐related epilepsies

Gallagher, D. et al. (2024) Genotype–phenotype associations in 1018 individuals with SCN1A‐related epilepsies. Epilepsia, 65(4), pp. 1046-1059. (doi: 10.1111/epi.17882) (PMID:38410936)

Abstract

Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype–phenotype associations remain poorly understood. Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4–S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. Significance: Understanding genotype–phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.

• Item Type: Articles
• Additional Information: A.B. and S.M.Z. received a grant from Dravet Syndrome UKfor the Glasgow SCN1A database (grant 16GLW00).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zuberi, Dr Sameer and Symonds, Dr Joseph and Brunklaus, Professor Andreas

Creator Roles

Symonds, J.: Writing – review and editing
Zuberi, S.: Investigation, Writing – review and editing
Brunklaus, A.: Project administration, Conceptualization, Supervision, Writing – review and editing, Funding acquisition, Methodology, Resources, Validation

• Authors: Gallagher, D., Pérez-Palma, E., Bruenger, T., Ghanty, I., Brilstra, E., Ceulemans, B., Chemaly, N., de Lange, I., Depienne, C., Guerrini, R., Mei, D., Møller, R. S., Nabbout, R., Regan, B. M., Schneider, A. L., Scheffer, I. E., Schoonjans, A.-S., Symonds, J. D., Weckhuysen, S., Zuberi, S. M., Lal, D., and Brunklaus, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Epilepsia
• Publisher: Wiley
• ISSN: 0013-9580
• ISSN (Online): 1528-1167
• Published Online: 27 February 2024
• Copyright Holders: Copyright © 2024 The Authors
• First Published: First published in Epilepsia 65(4):1046-1059
• Publisher Policy: Reproduced under a Creative Commons license